Project Summary Neonatal Abstinence Syndrome (NAS) has skyrocketed in recent years as a result of the opioid epidemic plaguing this country. Since 2000, the number of babies affected by NAS has increased nearly 5-fold. Every 25 minutes a baby is born suffering from opioid withdrawal, often prematurely with developmental problems and potential long-term adverse effects including cognitive impairment. Approximately 5% of pregnant women abuse 1 or more substances, with nearly 20% of teenage pregnancies affected. In addition, medically supervised maintenance therapy with methadone or buprenorphine of pregnant women (~50,000 cases per year) also causes NAS and the need for hospitalization under emergency care with only palliative treatments available. To prevent NAS altogether, an effective therapy applied to the pregnant mother could be an opioid antagonist that does not enter the mother's brain ? i.e., does not affect opioid maintenance - but does penetrate the placenta and enters the fetal brain because of its immature blood brain barrier (BBB). This approach has the potential not only to suppress NAS symptoms after birth, but also to prevent developmental abnormalities and premature birth as a result of opioid exposure. The risks and costs associated with developing new therapies for pregnant women make it unlikely that any traditional pharmaceutical or biotechnology company will embrace NAS as a therapeutic indication. We have developed a potent peripherally-selective neutral antagonist of the mu-opioid receptor, 6?-naltrexol (6BN), with good oral bioavailability in animal models. 6BN is the main metabolite of naltrexone, which has been administered to pregnant women to block opioid abuse, without obvious adverse effects to the newborn (naltrexone readily enters the adult brain). Importantly, in a mouse model, 6BN crosses the placenta and is able to enter the fetal brain at high levels, but is relatively excluded from entering the maternal brain (as shown in humans). We have also demonstrated that 6BN prevents opioid dependence with high potency when co-administered with morphine in mouse pups (in mice the BBB does not fully close until post-natal day 20). The goal of this proposed work, using a guinea pig model, is to determine whether 6BN administered to the pregnant female has similar pharmacokinetic behavior displaying preferential access to the fetal brain over the maternal brain and is orally available, the preferred route for pregnant women (Phase I, Aim 1). If results meet our expectations, we will test the ability of 6BN to block opioid dependence (and subsequent NAS symptoms) selectively in the fetus and develop an optimized dosage regimen, as a proof-of-principle (Phase II, Aim 2). In addition, we will implement an IND-enabling toxicology program (Phase II, Aim 3). Project Summary | Page 1